PUBLICATION
SMYD1-mediated mono-methylation of lysine K35 of sarcomeric myosin heavy chain (MHC) regulates sarcomere assembly and homeostasis in zebrafish and human iPSC-derived cardiomyocytes
- Authors
- Diofano, F., Amadi, C., Hartmann, L., Gahr, B.M., Weinmann-Emhardt, K., Rottbauer, W., Just, S.
- ID
- ZDB-PUB-250920-10
- Date
- 2025
- Source
- Journal of Molecular and Cellular Cardiology : (Journal)
- Registered Authors
- Diofano, Federica, Gahr, Bernd, Just, Steffen
- Keywords
- Filament assembly, Homeostasis, Myosin heavy chain, Sarcomeres, Zebrafish, iPSc cardiomyocytes
- MeSH Terms
-
- Animals
- Histone-Lysine N-Methyltransferase*/genetics
- Histone-Lysine N-Methyltransferase*/metabolism
- Homeostasis*
- Humans
- Induced Pluripotent Stem Cells*/cytology
- Induced Pluripotent Stem Cells*/metabolism
- Lysine*/metabolism
- Methylation
- Myocytes, Cardiac*/cytology
- Myocytes, Cardiac*/metabolism
- Myosin Heavy Chains*/chemistry
- Myosin Heavy Chains*/metabolism
- Proteasome Endopeptidase Complex/metabolism
- Sarcomeres*/metabolism
- Zebrafish/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 40972758 Full text @ J. Mol. Cell. Cardiol.
Citation
Diofano, F., Amadi, C., Hartmann, L., Gahr, B.M., Weinmann-Emhardt, K., Rottbauer, W., Just, S. (2025) SMYD1-mediated mono-methylation of lysine K35 of sarcomeric myosin heavy chain (MHC) regulates sarcomere assembly and homeostasis in zebrafish and human iPSC-derived cardiomyocytes. Journal of Molecular and Cellular Cardiology. :.
Abstract
The SMYD family comprises a distinct class of lysine methyltransferases (KMTases) that methylate both histone and non-histone proteins. Among its five members (SMYD1-5), SMYD1 has been identified as a cardiac and skeletal muscle-specific KMTase that interacts with Myosin, in coordination with Unc45b and Hsp90a, to regulate thick filament assembly. However, the precise mechanism by which SMYD1 orchestrates Myosin assembly remains largely unknown. Here, we demonstrate that SMYD1 physically associates with the N-terminal region of several myosin heavy chain (MyHC) isoforms and specifically catalyzes the mono-methylation of MyHC at lysine 35 (K35). Methylated MyHC is correctly incorporated into sarcomeres, whereas unmethylated MyHC in Smyd1-deficient zebrafish undergoes degradation via the ubiquitin-proteasome system (UPS), leading to defective thick filament assembly. Although UPS inhibition with MG132 restores Myosin levels in Smyd1-deficient zebrafish embryos, proper thick filament assembly remains impaired due to the absence of K35 MyHC mono-methylation. Similar to zebrafish striated muscle cells, SMYD1-mediated MyHC methylation is essential for thick filament assembly but also homeostasis in human cardiomyocytes, indicating a conserved cross-species mechanism of Myosin regulation, first described nearly 40 years ago. Further research is now required to explore the therapeutic potential of targeting this pathway in cardiomyopathies and skeletal muscle disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping